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P077 Effects of il-17 and the hepatocyte–mononuclear cell interactions in the hepatic inflammatory response
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  1. A Beringer1,
  2. ND Thiam1,
  3. J Molle2,
  4. B Bartosch2,
  5. P Miossec1
  1. 1Immunogenomics and Inflammation Research Unit EA4130, University of Lyon
  2. 2Inserm U1052, Cancer Research Centre, Lyon, France

Abstract

Introduction Interleukin-17A (IL-17), tumour necrosis factor-α (TNFα) and IL-6 are pro-inflammatory cytokines involved in many autoimmune and inflammatory diseases including rheumatoid arthritis. Because most acute-phase proteins are produced by the liver, the hepatic response plays an important role in systemic inflammation. By producing chemokines such as CCL-20 that attract Th17 cells, hepatocytes can recruit mononuclear cells in liver, which leads to chronic hepatitis.

Objectives To determine the effect of the IL-17/TNFα combination and the contribution of hepatocyte–peripheral blood mononuclear cell (PBMC) interactions in the hepatic inflammatory response.

Methods Human HepaRG cell line and primary human hepatocytes (PHH) were cultured with or without IL-6, anti-IL-6 receptor (anti-IL-6R) antibody, IL-17 and/or TNFα. For co-cultures, PBMC from healthy donors activated or not with phytohemagglutinin (PHA) were added on hepatocytes at a 5:1 ratio. Transwell system was used to study the contribution of the direct cell-cell contact. Cytokine expression and production were quantified by qRT-PCR and ELISA respectively and the secretion of C-reactive protein (CRP) by an automated analyzer.

Results IL-17 and TNFα induced in synergy the hepatic IL-6 production (>8 fold, p<0.01) and CCL-20 expression (>100 fold, p<0.01). CRP secretion was induced by IL-17/TNFα and the anti-IL-6R inhibited this induction. CCL-20 expression was not increased by IL-6 stimulation or reduced by the addition of the anti-IL-6R to the IL-17/TNFα treatment. In HepaRG cell-PBMC cultures, IL-6 and IL-17 were produced only in PHA-activated conditions and the IL-6 and IL-17 levels were higher in co-cultures vs PBMC monocultures (>14 and >2 fold respectively, p<0.01). Transwell system that avoids direct cell-cell contact decreased the IL-6 and IL-17 secretion by 4- and 2-fold respectively in PHA-activated HepaRG cell-PBMC cultures. CRP production increased when PHH were cultured in presence of PHA-activated PBMC compared to PHH alone with PHA.

Conclusions The IL-17/TNFα synergistic effect on hepatocytes mediates systemic inflammation by inducing CRP secretion through the IL-6 pathway and mononuclear cell recruitment by acting on CCL-20 expression in an IL-6 independent manner. Direct and indirect hepatocyte-PBMC interactions contribute to the hepatic inflammatory response by increasing the IL-6 and IL-17 secretion. The induction of Th17 cell differentiation by IL-6 and the increase of CCL-20 mediated Th17 cell recruitment by IL-17 may lead to a vicious and chronic inflammatory cycle.

Disclosure of interest None declared

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